Abstract Mounting evidence suggests that the aggregation of islet amyloid polypeptide (IAPP) is associated with ?-cell death in type-2 diabetes (T2D). IAPP, a 37-residue peptide hormone secreted by ?-cells, readily forms amyloid fibrils in vitro at M concentrations. The aggregates of IAPP, either insoluble amyloid fibrils or soluble oligomers, are found toxic to ?-cells. Inhibition of IAPP aggregation is an attractive therapeutic strategy to prevent ?-cell death and stop the progression of diabetic conditions in T2D. Interestingly, no apparent IAPP aggregates are observed in healthy individuals where IAPP is stored in ?-cell granules at mM concentrations. Therefore, physiological conditions of ?-cell granules natively inhibit amyloid aggregation of IAPP. Disruption of the inhibitive environment of ?-cell granules may lead to the accumulation of toxic IAPP aggregates, causing ?- cell death and the diabetic condition of insulin deficiency in T2D. Molecular mechanisms of the native inhibition of hIAPP aggregation are largely unknown, which limit the design of novel therapeutic approaches that either promote or mimic the native inhibition. In addition, several naturally-occurring small-molecule polyphenols displayed inhibitory effects on hIAPP aggregation. However, many of these small molecules have low water solubility, which limits their bioavailability and biodistribution. Knowledge of the mechanism of action of these polyphenols may help design de novo small-molecule drugs that can inhibit hIAPP aggregation with higher efficacy and solubility. Further more, our preliminary studies combining in silico modeling with in vitro and ex vivo characterization indicated that the generation-3 polyamidoamin (PAMAM) dendrimer, a polymeric nanoparticle commonly used for drug delivery, could also inhibit hIAPP aggregation. Our results pointed to a promising nanomedicinal approach for both efficient loading of ant-amyloid drug and inhibitory effect on hIAPP aggregation. In this MIRA application, the PI proposes the following three projects to uncover various inhibition mechanisms of hIAPP aggregation: 1) to delineate the inhibitive mechanism of the environmental elements of granules on IAPP aggregation; 2) to uncover the inhibition mechanism of hIAPP aggregation by small-molecule polyphenols; and 3) to explore dendritic nanoparticles with increased small-molecule loading and inhibitive effects on hIAPP aggregation. The PI lab will combine computational modeling with experimental characterization and validation. Computational modeling can help bridge the gaps of time and length scales between experimental observations and the underlying molecular systems, providing not only molecular insight to experimental observations but also offering experimentally-testable hypotheses. Such a combined computational and experimental approach can improve research efficiency and shorten discovery cycle. The outcome of the proposed studies will help design therapeutic strategies to either promote or mimic the native inhibition (Project 1), novel small-molecule inhibitors with enhanced anti-amyloid efficacy (Project 2), and engineered NPs with both high drug delivery and enhanced anti-aggregation properties (Project 3).